Corneal Abnormalities Are Novel Clinical Feature in Wolfram Syndrome

Am J Ophthalmol. 2020 Sep:217:140-151. doi: 10.1016/j.ajo.2020.04.012. Epub 2020 Apr 23.


Purpose: To evaluate corneal morphology among patients with Wolfram syndrome (WFS).

Design: Comparative observational longitudinal case series of WFS patients with a laboratory approach in the WFS1 gene knockout (Wfs1KO) mouse model.

Methods: A group of 12 patients with biallelic mutations in the WFS1 gene recruited from the whole country and a control group composed of 30 individuals with type 1 diabetes (T1D) were evaluated in a national reference center for monogenic diabetes. All subjects (n = 42) underwent a complete ophthalmic examination, computer videokeratography, and corneal thickness and endothelial measurements. Additionally, WFS patients (n = 9) underwent longitudinal videokeratography and Pentacam evaluation. Corneal characteristics were assessed and compared between both groups. Human and mouse corneas were subjected to immunohistochemistry to detect wolframin expression and microscopic evaluation to study corneal morphology ex vivo.

Results: Clinical and topographic abnormalities similar to keratoconus were observed in 14 eyes (58.3%) of 8 WFS patients (66.7%). Flat keratometry, inferior-superior dioptric asymmetry, skewed radial axis, logarithm of keratoconus percentage index, index of surface variance, index of vertical asymmetry, keratoconus index, central keratoconus index, index of height asymmetry, and index of height decentration differed between WFS and T1D patients. Immunohistochemistry demonstrated wolframin expression in human and mouse corneas. Compared with Wfs1WT mice, Wfs1KO mice also presented corneal abnormalities.

Conclusions: Patients with WFS present a high prevalence of changes in corneal morphology compatible with the diagnosis of early stages of keratoconus. Observations in a mouse model suggest that a mutation in the WFS1 gene may be responsible for corneal abnormalities similar to keratoconus.

Publication types

  • Comparative Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Cornea / pathology*
  • Corneal Diseases / diagnosis*
  • Corneal Diseases / etiology
  • Corneal Diseases / physiopathology
  • Corneal Pachymetry
  • Corneal Topography / methods*
  • Female
  • Humans
  • Male
  • Mice
  • ROC Curve
  • Retrospective Studies
  • Wolfram Syndrome / complications*
  • Wolfram Syndrome / diagnosis
  • Wolfram Syndrome / physiopathology
  • Young Adult